title: Gene expression profiling specifies chemokine, mitochondrial and lipid metabolism signatures in leprosy.
abstract: Herein, we performed microarray experiments in Schwann cells infected with live M. leprae and identified novel differentially expressed genes (DEG) in M. leprae infected cells. Also, we selected candidate genes associated or implicated with leprosy in genetic studies and biological experiments. Forty-seven genes were selected for validation in two independent types of samples by multiplex qPCR. First, an in vitro model using THP-1 cells was infected with live Mycobacterium leprae and M. bovis bacillus Calmette-Guérin (BCG). In a second situation, mRNA obtained from nerve biopsies from patients with leprosy or other peripheral neuropathies was tested. We detected DEGs that discriminate M. bovis BCG from M. leprae infection. Specific signatures of susceptible responses after M. leprae infection when compared to BCG lead to repression of genes, including CCL2, CCL3, IL8 and SOD2. The same 47-gene set was screened in nerve biopsies, which corroborated the down-regulation of CCL2 and CCL3 in leprosy, but also evidenced the down-regulation of genes involved in mitochondrial metabolism, and the up-regulation of genes involved in lipid metabolism and ubiquitination. Finally, a gene expression signature from DEG was identified in patients confirmed of having leprosy. A classification tree was able to ascertain 80% of the cases as leprosy or non-leprous peripheral neuropathy based on the expression of only LDLR and CCL4. A general immune and mitochondrial hypo-responsive state occurs in response to M. leprae infection. Also, the most important genes and pathways have been highlighted providing new tools for early diagnosis and treatment of leprosy.
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, FIOCRUZ-RJ, Rio de Janeiro, Brazil.
authors.forename: Luana Tatiana Albuquerque
authors.initials: LT
authors.lastname: Guerreiro
authors.forename: Anna Beatriz
authors.initials: AB
authors.lastname: Robottom-Ferreira
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ribeiro-Alves
authors.forename: Thiago Gomes
authors.initials: TG
authors.lastname: Toledo-Pinto
authors.forename: Tiana
authors.initials: T
authors.lastname: Rosa Brito
authors.forename: Patrícia Sammarco
authors.initials: PS
authors.lastname: Rosa
authors.forename: Felipe Galvan
authors.initials: FG
authors.lastname: Sandoval
authors.forename: Márcia Rodrigues
authors.initials: MR
authors.lastname: Jardim
authors.forename: Sérgio Gomes
authors.initials: SG
authors.lastname: Antunes
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Shannon
authors.forename: Euzenir Nunes
authors.initials: EN
authors.lastname: Sarno
authors.forename: Maria Cristina Vidal
authors.initials: MC
authors.lastname: Pessolani
authors.forename: Diana Lynn
authors.initials: DL
authors.lastname: Williams
authors.forename: Milton Ozório
authors.initials: MO
authors.lastname: Moraes
mesh_terms: D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D007918:Leprosy / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D050356:Lipid Metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000382:microbiology; D009163:Mycobacterium bovis / Q000276:immunology; D009166:Mycobacterium leprae / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D010525:Peripheral Nerves / Q000378:metabolism; D012583:Schwann Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D059467:Transcriptome
chemical_list: D018925:Chemokines